Method for the reduction of oxygenated compounds of rhenium or technetium

ABSTRACT

The present invention relates in general to a method for the reduction of oxygenated compounds of rhenium and technetium and in particular to the reduction of perrhenate or pertechnetate ions. 
     More particularly, the invention relates to reactions for the reduction of the said oxygenated compounds which are carried out in the course of the preparation of complexes of the radionuclides  186  Re,  188  Re and  99m  Tc; in these reactions, the radionuclide perrhenate or pertechnetate ion is reduced in the presence of a reducing agent and a ligand which can form a complex with the radionuclide in its reduced oxidation state.

This application is a 371 of PCT/EP97/05448 filed Oct. 3, 1997.

The present invention relates in general to a method for the reductionof oxygenated compounds of rhenium and technetium and in particular tothe reduction of perrhenate or pertechnetate ions.

More particularly, the invention relates to reactions for the reductionof the said oxygenated compounds which are carried out in the course ofthe preparation of complexes of the radionuclides ¹⁸⁶ Re, ¹⁸⁸ Re and^(99m) Tc; in these reactions, the radionuclide perrhenate orpertechnetate ion is reduced in the presence of a reducing agent and aligand which can form a complex with the radionuclide in its reducedoxidation state.

It is known that the radionuclides ¹⁸⁶ Re, ¹⁸⁸ Re and ^(99m) Tc havenuclear properties which make their coordination compounds suitable forapplication in nuclear medicine as therapeutic and diagnostic agents.Although the similarity between the chemical properties of technetiumand rhenium lead one to think that a method of synthesising ^(99m) Tcradiopharmaceuticals might simply be transferred to the preparation ofsimilar tracers of ¹⁸⁶ Re and ¹⁸⁸ Re, there are, however, fundamentaldifferences between the properties of the two elements such as to makethe possible use of rhenium compounds in nuclear medicine subject tocertain conditions.

In fact, since the metals technetium and rhenium in their highestoxidation states and, in particular, the tetraoxygenated anions [MO₄ ]⁻(M=Re, Tc) are the principal starting materials for the synthesis ofradiopharmaceuticals of rhenium and technetium, the result is that thereduction potentials of these species play a very important role indetermining the course of the synthesis reactions. In particular, it isknown that the reduction potential of the pertechnetate anion isconsiderably greater than that of the perrhenate anion. This indicatesthat, once a given synthesis has been determined, it must be much easierto prepare a technetium complex than the analogous rhenium complex.

In general, it is possible for a given synthesis adopted to obtain aradiopharmaceutical from ^(99m) Tc give a very much lower reaction yieldin the case of rhenium. This conclusion is even more significant whenone considers that, in the therapeutic application of rhenium compounds,the final product must have a very high radiochemical purity to reduceradiological risks.

The considerations set out above show that, to produceradiopharmaceutical preparations involving metal complexes of theradionuclides ¹⁸⁶ Re and ¹⁸⁸ Re, it is necessary to provide a method ofsynthesis which is very efficient at reducing the perrhenate ion.

U.S. Pat. No. 4,455,291 discloses that various "accelerators" are usefulto facilitate the preparation of cationic ^(99m) Tc complexes.Accelerators include oxalic acid, tartaric acid and ascorbic acid.

U.S. Pat. No. 4,871,836 discloses that ¹⁸⁶ Re/¹⁸⁸ Re kits can usefullycontain an "accelerator (catalyst)", preferably citric acid, tartaricacid and malonic acid. Example 9 discloses a freeze-dried kit for thepreparation of ¹⁸⁶ Re complexes from perrhenate which includes bothcitric acid and cyclodextrin in the formulation. The cyclodextrin isdescribed as a solubiliser.

U.S. Pat. No. 5,026,913 discloses that cyclodextrins can be used assolubilisers in kits for the preparation of _(99m) Tcradiopharmaceuticals.

U.S. Pat. No. 5,300,280 discloses a method of stabilisingradiopharmaceutical kits using cyclic oligosaccharides (cyclodextrins)to inhibit oxidation and/or volatilisation of the kit components. ¹⁸⁶Re, ¹⁸⁸ Re and ^(99m) Tc are specifically claimed.

DD 265628 discloses a method for the production of in vivo stable ^(99m)Tc pertechnetate crown ether coordination compounds, wherein crownethers are reacted stoichiometrically with Sn²⁺ cations and sodium_(99m) Tc-pertechnetate is added in a stoichiometric amount.

A specific object of the present invention is to provide a moreefficient method for the reduction of oxygenated compounds of rheniumand, in particular, of the perrhenate ion.

Another object is to provide a general method of synthesis ofradiopharmaceuticals of rhenium, applicable to the preparation ofdifferent classes of compounds under sterile and apyrogenic conditions.

With reference to technetium, although its reduction potential is morefavourable than that of rhenium, its reduction in the presence ofspecific ligands'to form a complex may be very difficult depending uponthe specific ligand used. For this reason, there is also a need toprovide a more efficient method of reducing technetium which facilitatesthe formation of the desired complex without the need to adoptparticularly drastic reduction conditions and a further object of thepresent invention results from this need.

In view of the aforesaid objects, a subject of the present invention isa method for the reduction of oxygenated compounds of rhenium ortechnetium, carried out in the presence of a reducing agent, wherein thereduction is carried out in the presence of a macromolecular compoundselected from the group consisting of cyclic oligosaccharides, crownethers and cryptands, said macromolecular compound being effective todisplace the equilibrium of the reduction reaction toward the formationof the reduced species of the rhenium or technetium.

The reduction process to which the invention relates, makes use of thesupramolecular interactions known as host-guest interactions. It isknown that a host-guest interaction consists of the formation of asupramolecular aggregate of two species, of which the first (host) ischaracterised by the presence of a molecular cavity sufficiently largeto house the second (guest) which is of smaller dimensions. The forceswhich cause the smaller molecule to be trapped generally belong to thecategory of weak interactions (van der Waals interactions, hydrogenbonding, hydrophilic and hydrophobic interactions, London forces) andthus do not alter the chemical nature of the species enclosed in thecavity.

The host molecules used in the process of the invention include cyclicoligosaccharides such as, in particular, modified or unmodifiedcyclodextrins, crown ethers and cryptands.

The modified or unmodified cyclodextrins usable in the invention includeα-cyclodextrins, β-cyclodextrin, γ-cyclodextrin and their mixtures.γ-cyclodextrins are particularly preferred.

By way of example, hydroxypropyl-α-cyclodextrin andhydroxyethyl-α-cyclodextrin may be used as the α-cyclodextrin;hydroxypropyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin,dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin,2,6-di-o-methyl-β-cyclodextrin and sulphated β-cyclodextrin may be usedas the β-cyclodextrin; hydroxypropyl-γ-cyclodextrin,dihydroxypropyl-γ-cyclodextrin; hydroxypropyl-γ-cyclodextrin andsulphated γ-cyclodextrin may be used as the γ-cyclodextnin.

A full review of the cyclodextrins usable as host molecules insupramolecular structures is provided in the article by G. Wenz inAngew, Chem. Int. ed. engl., 1994, 33, 803-822 incorporated herein byreference.

As crown ethers there may be used crown ethers available commerciallyand their derivates such as, for example, the compounds given in theFluka 1995/96 catalogue, p 419, among which in particular are the12-crown-4, 15-crown-5 and 18-crown-6 ethers and their derivatives.

It is understood that, in embodiments of the invention which relate tothe production of radiopharmeceutical complexes, the host molecules usedmust be pharmaceutically acceptable.

The quantity of host molecule used in the process of the invention isnot particularly critical and is generally in the stoichiometric ratioor in excess with respect to the rhenium or technetium. The reducingagents which may be used within the scope of the invention are anyreducing agents able to reduce the compound or anion of rhenium ortechnetium. The preferred reducing agents for the perrhenate andpertechnetate anions comprise Sn²⁺, Fe²⁺ and Cu¹⁺, of which the stannousion, which is widely used in radiopharmaceutical preparations, ispreferred. These ions may be introduced into the reaction medium in theform of halides, particularly the chlorides, or in the form of inorganicsalts such as phosphonates and organic salts, particularly salts ofpolycarboxylic acids, such as tartrates, citrates, oxalates, gluconatesand glucoheptanates. Other reducing agents include phosphines, such astriphenylphosphine, tris(2-sulphonatophenyl)phosphine,tris(cyanoethyl)phosphine, sodium borohydride, alkali metalthiosulphates, dithionites and dithionates.

According to a preferred embodiment, the reduction reaction is carriedout in the presence of a polycarboxylic acid or metal salt thereof(preferably an alkali metal salt), such as oxalate, citrate, ascorbate,malonate or tartrate, which acts as a secondary reducing agent. Oxalateis highly preferred.

The ligands used in the invention include ligands used inradiopharmaceutical kits such as, for example, phosphines, phosphonates,arsines, thiols, thioethers, isonitriles, amines, cyclic amines,polyamines, dithiocarbamates, dithiocarboxylates, Schiff bases,diaminodithiols, bis(amino)thiols, oximes, sugars, borates, amino acids,polyamino acids, ligands including combinations of these groups andpeptide ligands. In general the ligand may comprise any molecule thathas atoms which are able to coordinate with the central rhenium ortechnetium metal ion to form a stable complex or a complex which cangive rise to substitution reactions with other ligands.

It is also possible to use the methods described in the invention toproduce radiopharmaceuticals of ¹⁸⁶ Re and ¹⁸⁸ Re, characterised by thepresence, in the structure of the complex, of the terminalrhenium-nitride triple bond, Re.tbd.N, through the use of suitable donormolecules of nitride groups N³⁻ such as hydrazine, hydrazinederivatives, derivatives of dithiocarbazic acid, sodium azide and, ingeneral, molecules containing the functional >N--N< group.

One embodiment of the invention includes the choice of coordinatingligands which satisfy one or both of the following requisites:

a) the ligand fused promotes the stabilisation of the reduced specieswhich forms as a result of the reduction of the perrhenate orpertechnetate ion; and

b) forms a complex with the reduced species which can give rise to asubstitution reaction with other ligands.

The requisite b) takes account of the fact that the coordinationcompound produced by the method given by the above process, andcontaining the metal ion in a lower oxidation state, in turn constitutesa pre-reduced intermediate through which it is possible to obtain thefinal complexes by means of simple substitution reactions. In thisembodiment, it is preferable to use ligands, such as oxalate andcitrate, in the reduction reaction which are able to promote theelectroreduction of the [ReO₄ ]⁻ anion and which do not give rise tostable complexes with rhenium, particularly in oxidation states lessthan +7.

In this embodiment, the reaction is carried out in the presence of afirst ligand which satisfies requirements a) and b), particularlyoxalate and citrate, and a second ligand suitable for the preparation ofa specific radiopharmaceutical and capable of replacing completely thefirst ligand which coordinates weakly with the metal centre (i.e. liganddisplacement or transchelation).

Examples of phosphine ligands for use in radiopharmaceutical kitsinclude tris(3-ethoxypropyl)phosphine, trimethylphosphine,triethylphosphine, tris(3-methoxy-3-methylbutyl)phosphine,tris(3-methoxypropyl)phosphine,tris[2-[2(1,3-dioxanyl)]]ethylphosphine,methylbis(3-methoxypropyl)phosphine, tris(4-methoxybutyl)phosphine,dimethyl(3-methoxypropyl)phosphine,methylbis[2-[2-(1,3-dioxanyl)]]ethylphosphine andbis(1,2-dimethylphosphine)ethane.

As peptide ligands there may, for example, be used the peptides modifiedwith a phosphine group described in European Patent Application EP-A-0659 764 in the name of the Applicant incorporated herein by reference.

The reduction reaction is generally carried out at a pH of between 1 and10, preferably at a physiological pH of between 5 and 8, more preferablyat a pH of from 5 to 6.

The possibility of working at a physiological pH, with a good yield, isa further advantage of the method of the invention.

The method of the invention will be further described by means of thefollowing examples and appended drawings.

In the drawings:

FIG. 1) shows time-activity curves representing the variation of thepercentage of [¹⁸⁸ ReO₄ ]⁻ activity in the course of the reactions:

(a) [¹⁸⁸ ReO₄ ]⁻ +SnCl₂ (0.2 mg)→[¹⁸⁸ ReO(DMSA)₂ ]⁻ and

(b) [¹⁸⁸ ReO₄ ]⁻ +SnCl₂ (0.2 mg)→+γ-cyclodextrin(10 mg)→[¹⁸⁸ ReO(DMSA)₂]⁻

FIG. 2) shows time-activity curves representing the variation of thepercentage of [¹⁸⁸ ReO₄ ]⁻ activity in the course of the reactions:

(a) [¹⁸⁸ ReO₄ ]⁻ +SnCl₂ (1.0 mg)→[¹⁸⁸ ReO(DMSA)₂ ]⁻ and

(b) [¹⁸⁸ ReO₄ ]⁻ +SnCl₂ (1.0 mg)+γ-cyclodextrin(10 mg)→[¹⁸⁸ ReO(DMSA)₂]⁻

FIG. 3) shows time-activity curves representing the variation of thepercentage of [¹⁸⁸ ReO₄ ]⁻ activity in the course of the reactions:

(a) [¹⁸⁸ ReO₄ ]⁻ +SnCl₂ (0.2 mg)→[¹⁸⁸ ReO(DMSA)₂ ]⁻ and

(b) [¹⁸⁸ ReO₄ ]⁻ +SnCl₂ (1.0 mg)+γ-cyclodextrin(10 mg)+oxalate(6mg)→[¹⁸⁸ ReO(DMSA)₂ ]⁻

EXAMPLE 1

To a vial containing 2.5 mg of dimercaptosuccinic acid (DMSA below),10.0 mg of γ-cyclodextrin and 92.0 mg of potassium oxalate were added1.0 mg of SnCl₂.2H₂ O dissolved in 0.10 ml of an aqueous solution ofacetic acid (20% v/v), which was followed by the addition of 0.4 ml ofan aqueous solution of acetic acid (20% v/v) and 0.250 ml of saline. Tothe resulting solution were added 0.250 ml of a solution eluted from a[¹⁸⁸ Re] [ReO₄ ]⁻ generator (activity in the range 50 to 500 MBq) (pH=5.5) and the vial was kept at ambient temperature (or at 100° C.). Theformation of the final complex [¹⁸⁶ ReO(DMSA)₂ ]⁻ occurred almostinstantaneously, with a radiochemical yield of more than 95%.

In the present example and in the following the resulting products werecharacterised by HPLC and TLC.

EXAMPLE 2

The procedure given in Example 1 was carried out in exactly the same waywith the addition, however, of 0.2 mg of SnCl₂.2H₂ O; the final complexformed almost instantaneously with a radiochemical yield of more than95%.

EXAMPLE 3

The procedure of Example 1 was carried out in exactly the same way withthe use, however, of 0.02 mg of SnCl₂ H₂ O; the formation of the finalproduct was complete after fifteen minutes with a radiochemical yield ofmore than 95%.

EXAMPLE 4

To a vial containing 10.0 mg of γ-cyclodextrin and 92.0 mg of potassiumoxalate were added 1.0 mg of SnCl₂.2H₂ O dissolved in 0.10 ml of anaqueous acetic acid solution (20% v/v), with the subsequent addition of0.40 ml of aqueous acetic acid solution (20% v/v) and 0.250 ml ofsaline. Subsequently there were added 0.250 ml of a solution eluted froma generator of [¹⁸⁸ Re] [ReO₄ ]⁻ (activity in the range 50 to 500 MBq)(pH =5.5) and the vial was kept at ambient temperature (or at 100° C.)for fifteen minutes. Finally there were added 1.25 mg of DMSA and theresulting mixture was kept at ambient temperature (or at 100° C.). Theformation of the final product [¹⁸⁶ ReO(DMSA)₂ ]⁻ was complete almostinstantaneously with a radiochemical yield of more than 95%.

EXAMPLE 5

The procedure of Example 4 was repeated in an identical manner, with theaddition, however, of 0.2 mg of SnCl₂.2H₂ O. The formation of the finalproduct was complete almost instantaneously with a radiochemical yieldof more than 95%.

EXAMPLE 6

The procedure of Example 4 was carried out in an identical manner withthe addition, however, of 0.02 mg of SnCl.sub..2H₂ O. The formation ofthe final product was complete after one hour with a radiochemical yieldof more than 90%.

EXAMPLES 7-13

The procedures of examples 1 to 6 were repeated in an identical mannerwith the use, however, of the ligands 3,6-diaza-1,8-octandithiol and3,7-diaza-1,9-nonadithiol instead of the DMSA. The radiochemical yieldswere greater than 95% in all tests.

EXAMPLE 14

Preparation of [¹⁸⁸ ReO(L)Cl]

To a vial containing 3.0 mg of LH₂ (LH₂=3-diphenylphosphinopropionylglycyl-L-(S-benzyl)cysteinyl methyl ester)dissolved in 0.10-ml of methanol, 10.0 mg of γ-cyclodextrin and 92.0 mgof potassium oxalate, there were added 1.0 mg off SnC₂.2H₂ O dissolvedin 0.20 ml of an aqueous acetic acid solution (20% v/v), with asubsequent addition of 0.30 ml of aqueous acetic acid (20% v/v). To theresulting mixture were added finally 0.500 ml of a solution eluted froma generator of [¹⁸⁸ Re] [ReO₄ ]⁻ (activity in the range 50 to 500 MBq)(pH =5.5) and the vial was kept at ambient temperature (or at 100° C.)for one hour. The formation of the final product gave a radiochemicalyield of more than 95%.

EXAMPLE 15

The procedure of Example 14 was repeated in exactly the same way withthe addition, however, of 0.2 mg of SnCl₂.2H₂ O. The formation of thefinal product gave a radiochemical yield of more than 95%.

EXAMPLE 16

Preparation of [¹⁸⁸ Re(O)(DMSA)₂ ]⁻

To a vial containing 6.0 mg of tris(2-sulphonatophenyl)phosphine sodiumsalt (TPPTS =[P(C₆ H₄ SO₃)₃ ]Na₃), 10.0 mg of γ-cyclodextrin, 92.0 mg ofpotassium oxalate, 0.50 ml of an aqueous acetic acid solution (20% v/v)and 0.250 ml of saline, there were added 0.250 ml of a solution elutedfrom a generator of [¹⁸⁸ Re] [ReO₄ ]⁻ (activity in the range 50 to 500MBq) (pH =5.0) and the vial was kept at ambient temperature (or at 100°C. respectively) for thirty minutes. There were then added 1.25 mg ofDMSA and the resulting mixture was maintained at 100° C. for thirtyminutes. The formation of the final product gave a radiochemical yieldof more than 95%.

EXAMPLE 17

Preparation of [¹⁸⁸ Re(O)(DMSA)₂ ]⁻

0.2 mg of SnCl₂ (dissolved in 0.5 mL of 20% aqueous glacial aceticacid), 10.0 mg of γ-cyclodextrin, 30.0 mg of sodium oxalate and 2.5 mgof H₂ DMSA were placed in a vial followed by 0.250 mL of [¹⁸⁸ ReO₄ ]⁻(50 MBq-500 MBq). The vial was kept at room temperature for 15 min.Yield>95%. ##STR1##

EXAMPLE 18

Preparation of [¹⁸⁸ Re(O)(BAT)]

0.2 mg of SnCl₂ (dissolved in 0.5 mL of 20% aqueous glacial aceticacid), 10.0 mg of γ-cyclodextrin, 30.0 mg of sodium oxalate and 2.0 mgof H₃ BAT were placed in a vial followed by 0.250 mL of [¹⁸⁸ ReO₄ ]⁻ (50MBq-500 MBq). The vial was kept at room temperature for 15 min.Yield>95%. ##STR2##

EXAMPLE 19

Preparation of [¹⁸⁸ Re(O)(L)Cl]

0.2 mg of SnCl₂ (dissolved in 0.5 mL of 20% aqueous glacial aceticacid), 10.0 mg of γ-cyclodextrin, 30.0 mg of sodium oxalate and 3.0 mgof LH₂ were placed in a vial followed by 0.250 mL of [¹⁸⁸ ReO₄ ]⁻ (50MBq-500 MBq). The vial was kept at room temperature for 30 min.Yield>95%. ##STR3##

EXAMPLE 20

Preparation of [¹⁸⁸ Re(O)(P₂ N,)C ]

0.2 mg of SnCl₂ (dissolved in 0.5 mL of 20% aqueous glacial aceticacid), 10.0 of γ-cyclodextrin 30.0 mg of sodium oxalate and 3.0 mg of P₂N₂ H₂ were placed in a vial followed by 0.250 mL of [¹⁸⁸ ReO₄ ]⁻ (50MBq-500 MBq). The vial was kept at room temperature for 15 min.Yield>95%. ##STR4##

EXAMPLE 21

Preparation of [¹⁸⁸ Re(N)(DEDC)_(2])

0.2 mg of SnCl₂ (dissolved in 0.5 mL of 20% aqueous glacial aceticacid), 10.0 of γ-cyclodextrin 30.0 mg of sodium oxalate and 1.0 mg ofN-methyl, S-methyl dithiocarbazate (H₂ NN(CH₃)C(S)SCH₃ were placed in avial followed by 0.250 mL of [¹⁸⁸ ReO₄ ]⁻ (50 MBq-500 MBq). The vial waskept at room temperature for 15 min. Successively, 5.0 mg ofdiethylenetriaminopentaacetic acid (DTPA) and 10.0 mg of the sodium saltof diethyldithiocarbamate (DEDC or [Et₂ NCS₂ ]Na) were added, and thevial was heated at 100 for 5 min. Yield>95%. ##STR5##

Other preparations have been carried out by adding the host molecule andthe secondary reducing agent Red to a commercial kit formulation of aspecific ligand before labelling with [¹⁸⁸ ReO₄ ]. This procedure hasbeen carried out with two commercial kit formulations for thepreparation of ^(99m) Tc-MDP and ^(99m) Tc-MAG3 radiopharmaceuticals.The detailed procedures are reported in the following examples.

EXAMPLE 22

Preparation of [¹⁸⁸ Re(MDP)]

0.2 mg of SnCl₂, dissolved in 0.5 mL of 20% aqueous acetic acid, 10.0 mgof γ-cyclodexttin 30.0 mg of sodium oxalate were added to a vialcontaining a commercial cold (i.e. non radioactive) kit formulation forthe preparation of ^(99m) Tc-MDP, followed by 0.250 mL of [¹⁸⁸ ReO₄ ]⁻(50 MBq-500 MBq). The vial was kept at room temperature for 15 min.Yield>95%. ##STR6##

EXAMPLE 23

Preparation of [¹⁸⁸ Re(O)(MAG3)]

0.2 mg of SnCl₂, dissolved in 0.5 mL of 20% aqueous acetic acid, 10.0 mgof γ-cyclodextrin and 5.0 mg of sodium oxalate were added to a vialcontaining a commercial cold kit formulation of ^(99m) Tc-MAG3, followedby 0.250 mL of [¹⁸⁸ ReO₄ ]⁻ (50 MBq-500 MBq). The vial was heated at100° C. for 15 min. Yield>95%. ##STR7##

The experimental results show that the method of the invention can besuccessfully applied to the labelling of various ligands., The yield offormation of the final complexes were always over 90%, and the labellingprocedures have been carried out under very mild conditions. Based onexperimental findings, the method appears to possess a wideapplicability.

The role played by the host molecule appears to be that of displacingthe equilibrium position of the reduction reaction towards the formationof the final product. This influence on the course of the reductionprocess can be envisaged by comparing the curves describing thedisappearance of the activity of [¹⁸⁸ ReO₄ ]⁻ as a function of time whenthe reactions of formation of the complex [¹⁸⁸ Re(O)(DMSA)]⁻ wereconducted both in the absence of γ-cyclodextrin and in the presence of10 mg of this compound.

FIG. 1 illustrates the comparison between the curves obtained using only0.2 mg of SnCl₂ and when 10.0 mg of γ-cyclodextrin were added to thepreparation.

It is apparent from FIG. 1 that, at the same reaction time, the processusing SnCl₂ in combination with γ-cyclodextrin is more displaced towardsthe formation of the product [¹⁸⁸ ReO(DMSA)₂ ]⁻ than that containingonly SnCl₂. More specifically, on approaching the equilibrium at longerreaction times (180 min.), the residual percentage of [¹⁸⁸ ReO₄ ]⁻remaining is always less when γ-cyclodextrin was present in the reactionprocedure in comparison with the situation where it was not utilized.This effect has been observed with all the ligands employed in thisstudy ranging from 50% to 15% depending on nature of the specific ligandand reaction conditions. It was particularly evident when the formationof the complex [¹⁸⁸ Re(DMSA)₂ ]⁻ was studied using 1.0 mg of SnCl₂ incombination with 10 mg of γ-cyclodextrin.

FIG. 2 reports the comparison between the time-activity curve obtainedwhen only 1.0 mg of SnCl₂ were employed and that where 10.0 mg ofγ-cyclodextrin were additionally used.

It is important to emphasize here that the effect of -displacingequilibrium exhibited by γ-cyclodextrin is maximum at longer reactiontimes (that is to say on approaching the-equilibrium of the reductionprocess), and is almost independent on the concentration ofγ-cyclodextrin. These findings strongly support the description of therole of the host species forming supramolecular aggregates with somerhenium or technetium intermediate complexes formed during the course ofthe reduction process. In terms of the activated complex theory,therefore, the effect of the host molecule can be described as due to alowering of the activation energy of the overall reduction processbrought about by the supramolecular interaction. Accordingly thefunction of the host molecule may be defined as a catalyst oraccelerator. The combination of Sn²⁺, oxalate and γ-cyclodextrin appearsto be the most efficient reduction procedure for [¹⁸⁸ ReO₄ ].

FIG. 3 compares the time-activity curve for-the reaction conducted usingonly 0.2 mg of SnCl, with that-obtained by including in the samereaction vial 6.0 mg of potassium oxalate and 10.0 mg of γ-cyclodextrin.

The invention also provides kits for the preparation ofradiopharmaceutical products `which include` one or more ligands able tobind to the radioactive rhenium or technetium metal, a reducing agent asdescribed above, a compound selected from the cyclic oligosaccharides,crown ethers or cryptands and pharmaceutically acceptable vehicles andauxiliary substances such as antioxidants, stabilisers and thickeners.The components of the radiopharmaceutical kit may be combined infreeze-dried form or may be kept separate to be combined at the momentof use. The radiopharmaceutical composition is formed by the addition ofthe radioactive agent obtained from the generator.

What is claimed is:
 1. A method for the reduction of an oxygenatedcompound of rhenium or technetium with a reducing agent, wherein thereduction reaction is carried out in the presence of a macromolecularcompound selected from the group consisting of cyclic oligosaccharides,crown ethers, and cryptands, wherein said macromolecular compound iseffective to displace the equilibrium of the reduction reaction towardthe formation of a reduced species of said oxygenated compound and thereducing agent is selected from the group consisting of Sn²⁺, Fe²⁺, andCu¹⁺ ions, and wherein the reducing agent is introduced into thereaction medium in the form of a halide, a phosphonate, or a salt of apolycarboxylic acid.
 2. A method for the reduction of an oxygenatedcompound of rhenium or technetium with a reducing agent, wherein thereduction reaction is carried out in the presence of a macromolecularcompound selected from the group consisting of crown ethers andcryptands, wherein said macromolecular compound is effective to displacethe equilibrium of the reduction reaction toward the formation of areduced species of said oxygenated compound.
 3. The method according toclaim 2 wherein the reduction is carried out in the presence of a ligandwhich can form a complex with the reduced species of the oxygenatedcompound of rhenium or technetium.
 4. The method according to claim 2,in which the oxygenated compound is perrhenate ion or pertechnetate ion.5. The method according to claim 2 wherein the reduction reaction iscarried out in the presence of a secondary reducing agent comprising apolycarboxylic acid or metal salt thereof.
 6. The method according toclaim 2, in which the reducing agent is selected from the ions Sn²⁺,Fe²⁺, and Cu¹⁺.
 7. The method according to claim 1, in which thepolycarboxylic acid salt is selected from the group consisting oftarrates, citrates, oxalates, gluconates, and glucoheptonates.
 8. Themethod according to claim 2, in which the reducing agent is selectedfrom the group consisting of phosphines, alkali metal thiosulphites,dithionites, alkali metal dithionites, and alkali metal borohydride. 9.The method according to claim 3, in which the ligand is selected fromthe group consisting of phosphines, arsines, thiols, thioethers,isonitriles, amines, cyclic amines, polyamines, dithiocarbamates,dithiocarboxylates, Schiff bases, diaminodithiols, bis(amino)thiols,oximes, sugars, borates, amino acids, polyamino acids, peptides,peptides modified with phosphine groups and ligands, and mixturesthereof.
 10. The method according to claim 9, in which the reductionreaction is carried out in the presence of a first ligand able topromote the stabilisation of the reduced state of the metal to form acomplex which can undergo substitution reactions with other ligands, andin the presence of a second ligand which can undergo said substitutionreaction with the first ligand to form a stable complex of the secondligand.
 11. A method for the reduction of an oxygenated compound ofrhenium or technetium with a reducing agent, characterised in that thereduction reaction is carried out in the presence of a macromolecularcompound selected from the group consisting of cyclic oligosaccharides,crown ethers, and cryptands, wherein said macromolecular compound iseffective to displace the equilibrium of the reduction reaction towardthe formation of a reduced species of said oxygenated compound, andwherein the reduction reaction is carried out in the presence of a firstligand able to promote stabilisation of the reduced state of the metalto form a complex which can undergo a substitution reaction with otherligands, and in the presence of a second ligand which can undergo saidsubstitution reaction with the first ligand to form a stable complex ofthe second ligand, said first ligand being a polycarboxylate compound.12. The method according to claim 11, wherein the polycarboxylatecompound comprises an oxalate or a citrate.
 13. The method according toclaim 2, wherein the reduction reaction is carried out at a pH of from 5to
 8. 14. A method of reducing a reaction time in a reaction for areduction of perrhenate ion or pertechnetate ion in the presence of areducing agent comprising using a macromolecular compound selected fromthe group consisting of crown ethers and cryptands.
 15. A method for thereduction of an oxygenated compound of rhenium or technetium with areducing agent, characterised in that the reduction reaction is carriedout in the presence of a macromolecular compound selected from the groupconsisting of cyclic oligosaccharides, crown ethers, and cryptands,wherein said macromolecular compound is effective to displace theequilibrium of the reduction reaction toward the formation of a reducedspecies of said oxygenated compound, and wherein the reduction iscarried out in the presence of a ligand selected from the groupconsisting of dimercaptosuccinic acid, 3,6-diaza-1,8-octanedithiol,3,7-diaza-1,9-nonanedithiol, and tris(2-sulphonatophenyl)phosphinesodium salt.